2-(tertiary-aminoalkyl)-2-(substituted-phenyl) ethylamines



Patented Nov. 14, 1950 2,530,126 2- (TERTIARY-AMINOALKYL) 2- (SUBSTI-TUTED-PHENYL) ETHYLAIWIN ES Charles Edward Kwartler, Albany, and PhilipLucas, Menands, N. Y., assignors to Sterling Drug Inc., Wilmington,Del., a corporation of Delaware No Drawing. Application June 29, 1946,Serial No. 680,524

9 Claims. (Cl. 260-5705) This invention relates to Z-(tert-aminoalkyh-Z-(aryDethylamines and to a method of preparing the same.

A large number of tert-aminoalkylamines has been described in theliterature; these diamines have been used as valuable intermediates inthe preparation of various pharmaceuticals, especially antimalarials.Also, there are known a few such diamines in which the alkyl residuebetween the tertiary and primary amine groupings is substituted by anaryl radical; but, in no instance, is the aryl radical in a betaposition to the primary amine group.

We have now found that diamines having the general formulaY=NR,--CH(Ar)CH2NHz, wherein Y=N- is a low molecular tert-amino group, Ris an aliphatic bridge, that is, a low molecular divalent aliphaticradical, and Ar is an aromatic radical, are valuable intermediates inthe synthesis of anti-infective agents such as those disclosed in ourcopending application Serial No. 680,523 filed June 29, 1946, and otherpharmaceuticals.

In the above general formula, Y=N- is a tertamino group derived from alow molecular secamine having the general formula YNH and containing noactive hydrogen atom other than the amino-hydrogen; such amines includedimethylamine, diethylamine, dipropylamine, methylbutylamine,piperidine, morpholine, and the like. In other words, Y=N is a lowerdialkylamino radical in which the alkyl groups may be joined to form aheterocyclic radical of the group consisting of piperidines andmorpholines. R is a low molecu ar divalent aliphatic radical whichconveniently may be designated as an aliphatic bridge. The bridge is achain of from two to seven atoms separating the tert-amino and thearylethylamine residues, and may contain interrupting O, S, -S, SO2-, or-N(alkyl)- groups. Thus, R. represents such bridges as: CH2CH2+,CH2CH2CH2, --CI-IzCI-IzCHzCI-Iz-, CHzCH (CI-I3) CH2CH2CH2SCH2CH2CH2-,and the like. 01', in other words, R is an alkylene group having 2 to '7atoms wherein the two free valences of said alkylene group are separatedby at least two contiguous carbon atoms. Ar is a 1 to 2 ringedcarbocyclic aromatic radical, including phenyl,

naphthyl and substituted derivatives thereof- Substituents of saidaromatic radicals may include: hydrocarbon groups, such as alkyl,aralkyl, aryl, and the like; halogen atoms, such as chlorine, bromine oriodine; tert-amino groups, such as diethylamino, piperidyl, morpholinyl,and the like; ether groups, such as alkoxy, aryloxy, and the like; orother similar groups which are unaifected by treatment with stronghalogenating agents, strong metalating bases, or hydrogen in thepresence of hydrogenation catalysts. The aromatic radical, Ar, may alsocontain other substituents which must be intermediately protected duringthe preparation of the diamine. For example, the hydroxyl group can beintermediately protected in the form of its ether derivatives. Inpracticing our invention we prefer to use as the group Ar, an aromaticmonocarbocyclic radical, which we define as an aromatic radical having abenzene nucleus which may bear substituents such as those indicatedabove.

We have further found that the diamines of the type disclosed above canbe prepared by first condensing a tert-aminoalkyl' Lhalide with anarylacetonitrile in the presence of a strong metalating base, such assodamide, followed by catalytic hydrogenation of the l-(tert-aminoalkyD-l-arylacetonitrile thus formed, according to the following equations.

where R, Y=N- and Ar have the meanings given hereinabove; X is a halogenatom such as chlorine, bromine or iodine; and. B is a. strong base,capable of metalating arylacetonitriles, such as alkali amides, alkalihydrides, and the like. In practicing our'invention we prefer to usesodamide as the base in the alkylation because of its availability andcheapness. We found that the l-(tert-aminoalkyl)1-arylacetonitrile canbe readily reduced to the corresponding diamine, preferably by catalytichydrogenation. We have had especially good results when thehydrogenation is conducted in 15% methanolic ammonia in the presence ofRaney nickel under 500 to 800 lbs. pressure of hydrogen at 30 to 50 C.

The following examples are presented to illustrate further ourinvention, but without any intention of restricting it thereto- Example1 (a) 3-dimethyIamino-1- phenylbutyronitrile- To a mixture of 72 g. ofZ-dimethylaminoethyl chloride hydrochloride, dissolved in 250 ml. ofwater, and ml. of benzene is added with cooling and stirring 45 g. ofsodium carbonate. After shaking the mixture vigorously, the benzenelayer is separated and dried over sodium sulfate and potassiumcarbonate. To the filtered benzene solution of 2-dimethylaminoethylchloride is added 52.7 g. of phenylacetonitrile. Then 17.5 g. ofsodamide is added in portions, with stirring, over a period of about 45minutes, while maintaining the temperature at 30-40 C. during theaddition. The temperature is increased gradually and kept at '75-80 C.about 1 hours. The reaction mixture is cooled, covered with anatmosphere of nitrogen, and 200 ml. of water is added. The mixture isshaken vigorously, the benzene layer separated, dried over sodiumsulfate and filtered. After the benzene has been removed in vacuo, theresulting residue is distilled in vacuo, yielding a main fractiondistilling at 137-142 C. and 6 mm. This product, 3-dimethylamino-l-phenyl-butyro nitrile, redistills at 130 C. and 4 mm.The hydrochloride is formed by passing hydrogen chloride into a coldether solution of the redistilled base. After recrystallization fromacetone this salt weighs about 44 g. and melts at 163-5.

(b) 4-dimethylamino-2-phe ylbutylamine.-A solution of 25.5 g. of3-dimethylamino-1-phenylbutyronitrile hydrochloride in 200 ml. of 17%methanolic ammonia is hydrogenated in the presence of 20 g. of Raneynickel under 500 lbs. pressure of hydrogen at room temperature for 26hours. After the catalyst has been filtered oil and the solvent removedin vacuo, the resulting residue is distilled, yielding a main fractionof about 13 g. of 4-dimethylamino-2-phenylbutylamine distilling at 145C. and 13 mm.

Example 2 (a) 3 diethylamino 1 phenylbutyronitrile. -This compound wasreported by Eisleb (Ber. 743, 1433-50 (1941), who gave a boiling pointof '130-135 C. at 3 mm. Our product, prepared by condensing2-diethylaminoethyl chloride with phenylacetonitrile distills at 110 C.and 0.5 mm., and forms a hydrochloride salt melting at 115- 117 C.

(b) 4-diethylamino-2-phenyZbutyZamine.-A solution of 64.8 g. of3-diethylamino-1-phenylbutyronitrile in 350 ml. of 15% methanolicammonia is hydrogenated in the presence of 30 g. of Raney nickel for 21-hours at room temperature under 700 lbs. pressure of hydrogen. Afterfiltering the catalyst and removing the solvent the main fraction of theresidue distills at 1'74-6 C. and 27 mm., yielding about 61 g. of4-diethylamino-2-phenylbutylamine.

Example 3 (a) 1- (4-chlorophenyl) -3-diethylaminobutyronitrile.-Thispreparat on is carried out like Example 1, but using 2-diethylaminoethylchloride (from 129 g. of the hydrochloride), 237 ml. of benzene, 130 g.of 4-chlorophenylacetonitrile, and 29.2 g. of sodamide. After thesodamide addition, conducted over a period of 40 minutes while keepingthe temperature at 40-45 0., the reaction mixture is refluxed for 5 ,4hours. On working up the reaction mixture as above Example 1), about 138g. of 1-(4-chlorophenyl) -3-diethylaminobutyronitrile distilling about124-6 C. and 1 mm. is obtained.

(1)) 2- (4-chlorophenyl) -4-diethylaminobutylamine.This preparation iscarried out like the previous hydrogenations, but using 133.5 g. of 1-(4-chlorophenyl) -3-diethylaminobutyronitrile, 500 ml. of methanolicammonia and 15g. of Raney nickel. The resulting 2-(4-chlorophenyl)-4-diethylaminobutylamine weighs about 118 g. and distills at 113 C. and1 mm.

Example 4 (a) 3,4-dichZorophenylacetonitriZa-This compound is preparedin the usual manner by refluxing a water-alcohol solution of3,4-dichlorobenzyl chloride, sodium cyanide and a trace of sodium iodidefor 4 hours. The 3,4-dichlorophenylacetonitrile thus obtained is acolorless liquid distilling at 170 C. and 12 mm.

(b) 1-(3,4-dichlorophenyl) -3-dl'ethglamznob1ltyronitriZe.--This nitrileis prepared in a manner similar to previous examples, but usingZ-diethylaminoethyl chloride (from 169 g. of the hydrochloride), 310 ml.of benzene, 208 g. of 3,4-dichlorophenylacetonitrile, and 38.2 g. ofsodamide. The free base,1-(3,4-dichlorophenyl)3-diethylaminobutyronitrile, weighs about 137 g.and distills at C. and 0.5 mm.

(c) 2- (3,4-dz'chlorophenyl) -4-dz'ethylam2'nobutylamine.-Thishydrogenation is run like previous examples, but using 128 g. of1-(3,4-dichlorophenyl)-3-diethylaminobutyronitrile, 600 ml. of 15%methanolic ammonia and 30 g. of Raney nickel. The diamine, 2-(3.4-dichlorophenyll-4- diethylaminobutylamine, weighs about 124 g. anddistills at 125 C. and 1 mm.

Example 5 (a) 3-dz'ethylamino-1- (st-methoxyphenyl) butyrom'trzZe.Thisalkylation is run like previous examples, but using Z-diethylaminoethylchloride (from g. of the hydrochloride), 300 ml. of benzene, 161 g. of4-methoxyphenylacetonitrile, and 37.6 g. of sodamide. The basic nitrile,3 diethylamino-l- (4-methoxyphenyl) butyronitrile, distills at 120 C.and 0.5 mm. and weighs about 142 g.

The corresponding 4-benzyloxyphenylderivative can be prepared in asimilar manner using 4-benzyloxyphenylacetonitrile in place of 4-methoxyphenylacetonitrile. About 79 g. of 1-(4- benzyloxyphenyl) 3diethylaminobutyronitrile, distilling about 192 C. at 1 mm., is obtainedfrom 113 g. of 4-benzyloxyphenylacetonitrile.

(b) dzethylamino-Z- (st-methoxyphenyl) bu tyZamine-This hydrogenation isrun like previous examples, but using g. of 3-diethylamino-1 (4methoxyphenyl)butyronitrile, 650 m1. of 15% methanolic ammonia and 30 g.of Raney nickel. The crude product is carefully fractionated in vacuo,with the desired fraction of about 34 g. of4-diethylamino-2-(4-methoxyphenyl)-butylamine distilling at 133-6 C. and1 mm.

The corresponding 4-benzyloxyphenyl derivative can be prepared in asimilar manner using 1 (3-benzylophenyl) 3 diethylaminobutyronitrileinstead of 3-diethylamino-1-(4-methoxyphenyl)butyronitrile. About 160 gof 2-(4- benzyloxyphenyl) 4 diethylaminobutylamine, distilling about 194C. at 2 mm., is obtained from 213 g. of the corresponding nitrile.

4 diethylamino 2 (4-hydroxypheny1)butylamine, distilling about 192-4 C.at 2 mm., can be prepared by treatment of 2-(4-benzyloxyphenyl)-4-diethylaminobutylamine at 50 C. with 50 lbs. pressure of hydrogen inthe presence of palladium chloride and charcoal.

' Example 6 (a) 1 (4 chlorophenyl) 4 diethylaminoe oaZer0nitrz'le.To asolution of 75 g. of 3-diethylaminopropyl chloride and 87 g. of4-chlorophenylacetonitrile in 150 m1. of benzene is added in portionsover a period of 45 minutes 20 g. of -soda-. mide while keeping thetemperature at 40-50 C.

with external cooling when necessary. The mixture is then heated toreflux for 5 hours, cooled and covered with nitrogen. After water isadded and the mixture is shaken vigorously, the benzene layer isseparated and extracted with 10% hydrochloric acid. The acidic extractis washed with ether, made alkaline to phenolphthalein with sodiumhydroxide solution, and extracted with ether. The ether extract iswashed with water and saturated sodium chloride solution, and dried overpotassium carbonate. After removal of the ether in vacuo, the mainfraction, comprising 1- (4-ohlorophenyl) 4 diethylaminovaleronitrile andweighing about 88 g., distills at 138-9" C. and 0.5 mm.

(b) 2-(4-chlorophenyl) 5 diethylaminopentylamz'ne.'ihis hydrogenation iscarried out like previous examples, but using 87 g. of1-(4-chlorophenyl) i diethylaminovaleronitrile, 25 g. of Raney nickeland 600 ml. of 15% methanolic ammonia. The 2- l-chlorophenyl) 5diethylaminopentylamin distills at l234 C. and 0.5 mm. and weighs about75 g.

Instead of using the particular arylacetonitriles mentioned hereinabove,a thienylacetonitrile, a pyridylacetonitrile, a naphthylacetonitrile, orother arylaceto-nitriles may be employed, thereby obtaining thecorresponding 2-(tert-aminoalkyl) 2- (aryl) ethylamine.

Also, instead of using the particular tertaminoalkyl halide mentionedhereinabove, other tert-aminoalkyl halides, such as 3-piperidylpropylbromide, 4 morpholinylbutyl chloride, 3 (N-methyl-N-isobutylamino)propyl iodide, 2-(3-dimethylaminopropylthio)ethyl chloride, 2 (2-diethylaminoethoXy)-ethyl chloride,5-diethylaminopentyl chloride, and the like may be employed.

ihe diamines of the present invention contain one primary and onetertiary amino group, and these respective groups can be converted intovarious derivatives by suitable adaption of general procedures.

Thus, the primary amino group (HzN-) of the diamines is converted into aureido group (NH2CONH-) by heating to 9095 C. an aqueous solutioncontaining the diamine and a slight excess over theory of nitroureauntil evolution of gas ceases. In this fashion 4-diethylamino-2-phenylbutylamine gives 4-diethylamino-2-phenyl-l-ureidobutane, M. P.83-4 C.

Again, the primary amino group (H2N) of the diamines is converted intothe guanido group (NH2C(=NH)NI-I) by heating an aqueous mixturecontaining equimolecular quantities of a diamine and anS-znethylisothiourea salt (e. g. sulfate, hydroiodide, etc.) until theevolution of gas (methanethiol) ceases. In this fashion, l-diethylamino2 phenylbutylamine yields l diethylamino-l-guanido-2-phenylbutanesulfate, M. P.

146 0. (turns vitreous at a lower temperature) and 4-diethylaminol-guanido-Z-phenylbutane hydroiodide monohydrate, M. P. 91-3 C.,l-diethylamino 2 (4-chlorophenyl)butylamine yields A-diethylaminol-guanido 2-(4-chlorophenyl) butane hydroiodide, M. P. 935 C., and4-diethylamino-2-(3,4-dichlorophenyl) butylamine yields4-diethylan1ino-1-guanido 2-(3,4-dichlorophenyl) butane hydroiodidemonohydrate, M. P. 122-3 C.

The 2-(tert-aminoalkyl) Z-(aryl) ethylamines of the present inventionare suitable for use as chemical intermediates for the synthesis ofantiinfective agents and other pharmaceuticals either in the form of thefree bases, or the salts thereof with inorganic or organic acids. Hence,it will be understood that the free bases and the salts thereof areequivalents with respect to the instant invention. The term, 2(tert-aminoalkyl) 2 (ary1)ethylamine, as used in the appended claims,will therefore be understood to include, not only the free base, butalso a salt of the free base with an inorganic or organic acid.

We claim: 1. A member of the group consisting of compounds having theformula wherein Y=N is a low molecular dialkylamino radical in which thealkyl groups may be joined. to form a heterocyclic radical of the groupconsisting of piperidines and morpholines, R is an alkylene group having2 to 7 atoms wherein the two free valences of said alkylene group areseparated by at least two contiguous carbon atoms, Ar is a member of thegroup consisting of halophenyl, dihalophenyl, hydroxyphenyl andalkoxyphenyl and Z is a member of the group consisting of primary amino,guanido and ureido groups.

2. A compound having the formula (lower alkyl) 2NR-CH (Ar) CHzNHz whereR is an alkylene group having 2 to 7 carbon atoms wherein the two freevalences of said alkylene group are separated by at least two carbonatoms and Ar is a halophenyl radical.

3. A compound having the formula (lower alkyl) 2NRCH (Ar) CH2NH2 where Ris an alkylene group having 2 to 7 carbon atoms wherein the two freevalences of said alkylene group are separated by at least two carbonatoms and Ar is a dihalophenyl radical.

4. A compound having the formula (lower alkyl) 2NRCH (Ar) CHzNHz whereR. is an alkylene group having 2 to '7 carbon atoms wherein the two freevalences of said alkylene group are separated by at least two carbonatoms and Ar is an alkoxyphenyl radical.

5. A compound having the formula where R is an alkylene group having 2to 7 carbon atoms wherein the two free valences of said alkylene groupare separated by at least two carbon atoms and Ar is a hydroxyphenylradical.

6. d-diethylamino 2 (4-methoXyphenyDbutylamine.

7. 4-diethylamino 2 (4-hydroxypheny1)butylamine. r

8. l-diethylamino 2 (4-cholophenyDbutylamine.

9. 4diethylamino 2 (3,4-dichlorophenyD- butylamine.

CHARLES EDWARD KWARTLER. PHILIP LUCAS.

REFERENCES CITED The following references are of record in the file ofthis patent:

FOREIGN PATENTS Number Country Date 13,600 Great Britain June 12, 1907423,735 Great Britain Jan. 28, 1935 710,227 Germany Sept. 8, 1941 OTHERREFERENCES Degering, An Outline of Organic Nitrogen Cpds., Univ.Lithoprinters, Ypsilanti, Mich., 1945, para. 1571.

Kleiderer et al., P. B. 981 (Cfiice of the Publication Board, Dept. ofCommerce, Wash., D. 0.), page 97, January 25, 1946.

Certificate of Correction Patent No. 2,530,126 November 14, 1950 CHARLESEDWARD KWARTLER ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows:

Column 2, line 21, for that portion of the equation reading ArCh CNBread ATOH O'N B+ column 3, line 55, before Example insert an openingparenthesis; column 4:, line 47, for 1-(3-benzylopheny1) read1-(4-ben2yl0myphenyl); column 6, line 50, for l-cholophenyl) read(4-chZ0r0phen3 Z);

and that the said Letters Patent should be read as corrected above, sothat the same may conform to the record of the case in the PatentOflice.

Signed and sealed this 9th day of January, A. D. 1951.

[SEAL] THOMAS F. MURPHY,

Assistant Commissioner of Patents.

1. A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA